Friday, February 4, 2011

New brain metabolism and ketone review article

I recently received this new article that discusses in great detail what is known about brain metabolism as we age and the potential for alternative fuels to glucose to prevent or stabilize the progression of Alzheimer's disease:

"The recent development of 11C-acetoacetate as a ketone tracer for PET studies opens a new window to compare brain metabolism of glucose and ketones in the same individual. If brainketone metabolism is not lower in AD or is less affected than glucose metabolism, one potential strategy to improve brain fuel availability and reduce the risk of AD that has already been targeted in clinical studies would be to develop a way to safely and reliably provide the brain with ketones as an alternative fuel to glucose..."

"Whether or not mitochondrial dysfunction reflects genetic or metabolic disturbances,clinical trials attempting to redress the energy deficit in the AD brain suggest that cognitive function can be at least transiently improved if more fuel (glucose or ketones) can besupplied to the brain."

"In carriers of apo E4, small areas of lower brain glucose metabolism are observed at an ageas young as 30 y old, e.g., 30-40 y before clinical onset. Indeed, we see an inverse relationship between CMRg in several brain regions and fasting plasma insulin, so brain metabolismseems to be sensitive to even mild disturbances in systemic insulin control even if no clinical symptoms of cognitive decline are observed. Compared to non-carriers of apo E4, carriers have altered u3 [omega-3] fatty acid metabolism and higher measures of oxidative stress in the brain, both of which may contribute to a higher risk of early onset of brain hypometabolism. If brain hypometabolism can be present before clinical symptoms are apparent, this does not prove that hypometabolism is the earliest event in AD. However, to the best of our knowledge, hypometabolism is currently the earliest measurable abnormality in the brain that is connected to AD so its features and the reasons for it should shed light on the etiology of AD."

"The cerebral metabolic rate of ketones (CMRk) varies directlywith their blood concentration, starting at very low ketone concentrations...Hence, at a plasma b-hydroxybutyrate [one of the primary ketone bodies] concentration of 0.3-0.5 mM, such as can be achieved during 12-24 h fasting, b-hydroxybutyrate supplies 3-5% of whole brain energy requirements. As plasma ketones rise, CMRk also rises such that at a b-hydroxybutyrate of about 1.5mM, ketones provide about 18%, and at 6 mM, they provide about 60% of brain fuel." [Dr. Richard Veech's ketone ester can provide levels this high].

"Acute, controlled human experiments show that ketone infusion or ketogenesis inhibits the cognitive and behavioral sequelae of acute, experimental hypoglycemia, both in healthyadults and in type 1 diabetes. It is generally assumed that the cognitive effects of hypoglycemia can be prevented by ketones because they seamlessly replace glucose to meet the brain’s energy requirements. However, acutely raising plasma ketones also increases cerebral blood flow in humans, an effect that may contribute to their beneficial impact on cognition during hypoglycemia. Studies in humans and animal models suggest further protective effects of ketones in the brain after ischemic insult [lack of oxygen/stroke] and other treatments damaging neuronal function."

"More recent controlled clinical trials confirm that short-term improvement can occur in cognitive tests when individuals with mild to moderate AD are provided with an exogenous source of glucose, ketones, insulin, or insulin sensitizers. These clinical studies show that theaffected brain regions in AD are at least partially viable and that cognition can improve when exogenous fuel supply to the brain is increased. In two of these studies, ketogenic supplementsbased on medium chain triglycerides were used, thereby permitting a relatively normal choice of meals. Medium chain triglycerides have long been known to be ketogenic because they contain medium chain fatty acids (octanoic [8:0] and decanoic [10:0] acids), which do not require activation by CoA to enter mitochondria. The mild beneficial effects on cognition and relatively good tolerance to the doses of medium chain triglyceride used are promising, notwithstanding the possibility that carriers of apo E4 with AD derive little benefit from this treatment [Dr. Newport's comment: per one of the authors of the MCT oil studies, many of the ApoE4+ individuals did experience improvement, as a group when data was combined on the average they did not]. The explanation for the beneficial effect of mild, experimental ketonemia on cognition in AD may be as simple as exchanging one brain fuel for another as occurs infasting or starvation. It may also be due to the observation that although glycolysis may be impaired in the AD brain, CMRk and metabolic capacity to use a fuel other than glucose mayboth be relatively normal in AD."

"...two observations in particular support the notion that the neurons affected in AD are still functional: (1) in AD, brain ketone uptake is apparently normal or at least less impaired than is glucose, and (2) there is a functional response to nutritional supplements that increase brain fuelavailability, particularly ketones. Hence, if brain fuel metabolism could be optimized or even partially returned toward normal, the risk of further cognitive decline may diminish. Raising plasma ketones to 0.4-0.5 mM would contribute to 5-10% of the brain’s energy requirements, which is equivalent to the early cortical glucose deficit in those genetically at risk AD. Such a mild, safe level of ketonemia is achievable with ketogenic supplements, so if implemented before symptoms develop, it seems plausible that they could diminish the risk of further metabolic deterioration and clinical onset of cognitive decline."

Regarding Omega-3 fatty acids:

"The u3 [omega-3] polyunsaturated fatty acid, DHA, is now widely understood to have an important role in mammalian brain development...Insufficient dietary intake of DHA and low levels of DHA in the hippocampus may have a role in cognitive decline in the elderly and/or AD. Hence, the low intake of DHA now widely but not universally reported in AD may contribute to the evolution of cognitive decline because of its role in brain glucose transport and in other aspects of brain function and structure. This emerging role of DHA in brain energy metabolism could be linked to the early presymptomatic onset of brain glucose hypometabolism in AD, at least in carriers of the e4 allele of apoE4. Nevertheless, such an effect probably involves relatively subtle changes in DHA metabolism because plasma DHA appears to be higher in the healthy elderly and is widely variable in AD."

Dr. Newport's comments:

The bottom line here, to try to prevent or stabilize AD, include medium chain fatty acids (coconut oil, palm kernel oil and MCT oil are the richest sources) in the diet to provide ketones as an alternative fuel to glucose AND eat fish (especially salmon) and/or take a supplement of marine based omega-3 oil (fish oil for most of us; algae based oil for vegans found in brands that are marketed to pregnant women).

"Whether or not mitochondrial dysfunction reflects genetic or metabolic disturbances,clinical trials attempting to redress the energy deficit in the AD brain suggest that cognitive function can be at least transiently improved if more fuel (glucose or ketones) can besupplied to the brain."

Dr Newport, based on this point, I would understand the energy deficient AD brain performs better with a quick boost of energy. So why is Diabetes cited as a risk factor for AD? evidently I am missing some part of the puzzle, so please explain. I follow AD news and your website regularly since the incidence od AD in the menfolk of our family has been very-very high and am on the look out for any piece of understanding or information that will help.

Mayo Clinic researchers reported a strong relationship between celiac disease and declining brain function.... they report,cognitive impairment associated with celiac disease was never the initial clinical diagnosis. They further ask clinicians fora reevaluation of the role of celiac disease in causing cognitive impairment [as it] has the potential of expanding the narrow spectrum of treatable dementia.Also Hadsivasslliou has cured neurological problems with a gluten free diet .

I have read most of this blog and comments, and am distressed to see people recommending "diet" soda and Splenda to make coconut oil more palatable...

Please do the research on MSG and Aspartame.

These excitotoxins are insidious poisons which both cross the blood brain barrier and cause many of the diseases which Mary has noted in this blog:

On Aspartame truth:http://video.google.com/videoplay?docid=-6551291488524526735

http://www.dorway.com/

On MSG truth (and other "flavor enhancers" in processed foods):

http://www.msgtruth.org/http://www.mpwhi.com/main.htm

I know that it's nearly impossible at this time to find any chewing gum that DOESN'T contain aspartame for my son. That's telling...

Research aspartame and MSG (under it's myriad of names, added to ALL processed foods), then remove these poisons from your diet, to discover how well you can really feel, and what is REALLY causing diseases in the 1st world which don't exist in other places where people don't consume processed foods and aspartame...

Good luck.

Thanks to Dr. Mary: I watched the video on You Tube, researching ways to assist a couple of friends who suffer from AD, and it was helpful!

I notice that there is a post asking regarding chewing gum. Some years ago when I had a very dry mouth, my doctor suggested chewing gum. I mentioned this to another doctor and he told me that when you chew gum the stomach is expecting to receive food to process and activates some form of acid and then nothing arrives for the acid to breakdown. From this I assume he implied that chewing gum is not a good idea. Just passing this on for consideration.

Also for those trying coconut oil, I have noticed a significant improvement in bowel function from oil pulling. Use 2 tsps of coconut oil in the morning on an empty stomach prior to brushing teeth, drinking or eating. Swirl around in you mouth like a mouthwash and then spit it out. I then brush my teeth and use a tongue cleaner. From the very first day I was no longer constipated. Yet I had for about 2 months been eating coconut oil and during this time did not notice any improvement in bowel function. Feel it is worth read Bruce Fife's book The New Arthritis Cure. Yet from eating the coconut oil my TSH blood test went from 11.2 down to 5.8 in 6-7 weeks and my cholesterol ratio went from 4.2 down to 3.9. So while when only eating coconut oil did not aid constipation, it definitely had a positive effect.

Hi Dr. Newport,I would like to add my deep appreciation to those of many others, for your efforts in fighting AD. Like you, I believe that CO/MCTs are probably good (and tasty) prophylactic measure vs. other neurodegenerative disorders. Even though there is no AD or other such conditions in my family, some degree of short term memory loss comes with aging to all. After reading you blog and watching your YouTube presentation I added virgin coconut oil to my fresh coconut daily (delight) consumption (I live on a tropical island). Adding CO to melted square of unsweetened 100% cocoa chocolate, let it solidify in the fridge for a short time - is my way of taking it (I don't cook with any oil/fat at all).Best wishes for you and Steve.

About

About Me

Mary T. Newport, M.D. grew up in Cincinnati, Ohio, attended Xavier University and University of Cincinnati College of Medicine. She trained in Pediatrics at Children’s Hospital Medical Center in Cincinnati, and in Neonatology, the care of sick and premature newborns, at Medical University Hospital in Charleston, SC. She has practiced full-time neonatology in Florida since 1983 and was founding medical director for two newborn intensive care units in the Tampa Bay area. She has served as volunteer clinical faculty for University of South Florida. Dr. Newport has been married to Steve Newport since 1972 and they have 2 daughters, and a grandson. She wrote an article, “What If There Was a Cure for Alzheimer’s Disease and No One Knew?” relaying her research into a dietary intervention that produces mild ketosis that may benefit persons with Alzheimer’s and other neurodegenerative diseases. Her book was released in September 2011 from Basic Health Publications, Inc. (www.basichealthpub.com): "Alzheimer's Disease: What If There Was a Cure? The Story of Ketones". The 2nd edition will be available at the end of April 2013.